OptiTROP-Lung05 Shows PFS Benefit With First-Line Sac-TMT Plus Pembrolizumab in PD-L1+ NSCLC

The addition of the TROP2-directed antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT; SKB264/MK-2870) to pembrolizumab (Keytruda) significantly improved progression-free survival (PFS) vs pembrolizumab alone when used in the first-line treatment of patients with PD-L1–positive advanced non–small cell lung cancer (NSCLC), according to results from an interim analysis of the phase 3 OptiTROP-Lung05 study (NCT06448312).¹

The findings, which were presented at the 2026 ASCO Annual Meeting, and were simultaneously published in The Lancet,² showed that at a median follow-up of 10.5 months, the median PFS by blinded independent central review (BICR) was not reached (NR; 95% CI, 13.6-not evaluable [NE]) with sac-TMT plus pembrolizumab (n = 208) vs 5.7 months (95% CI, 4.3-7.0) with pembrolizumab alone (n = 205), translating to a 65% reduction in the risk of disease progression or death (HR, 0.35; 95% CI, 0.26-0.47; P < .0001).¹ The 12-month PFS rates were 62.4% and 29.0%, respectively.

“Results from the OptiTROP-Lung05 study support sac-TMT plus pembrolizumab as a potential new treatment option for first-line PD-L1–positive advanced NSCLC without EGFR or ALK alterations,” Caicun Zhou, of Shanghai East Hospital, Tongji University, in Shanghai, China, said in a presentation of the data.

How was the OptiTROP-Lung05 trial of sac-TMT plus pembrolizumab designed?

OptiTROP-Lung05 is a randomized, multicenter, open-label phase 3 study that enrolled patients with locally advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC who had not received prior systemic antitumor therapy. Patients did not have sensitizing EGFR or ALK alterations. Other eligibility criteria included having a PD-L1 tumor proportion score (TPS) of at least 1% by central immunohistochemistry 22C3 testing and an ECOG performance status no higher than 1.

A total of 413 patients were randomly assigned 1:1 to receive sac-TMT at 4 mg/kg every 2 weeks plus pembrolizumab at 400 mg every 6 weeks (n = 208) or pembrolizumab at 400 mg alone every 6 weeks (n = 205), with pembrolizumab given for a maximum of 18 cycles. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified by histology (squamous vs nonsquamous), PD-L1 TPS (1%-49% vs ≥ 50%), and ECOG performance status (0 vs 1).

The primary end point was PFS by BICR; a key secondary end point was overall survival (OS). Other secondary end points included investigator-assessed PFS, objective response rate (ORR), disease control rate, duration of response (DOR), and safety.

Baseline characteristics were generally balanced. The median age was 64 years (range, 28-75) in the combination arm and 65 years (range, 22-75) in the control arm. Approximately 84.5% of patients had an ECOG performance status of 1 (84.6%; 84.4%), and roughly 40% had squamous histology (40.9%; 39.0%). About 60% of patients had a PD-L1 TPS of 1% to 49% (60.1%; 60.0%) vs 40% with a TPS of at least 50% (39.9%; 40.0%). At the data cutoff date of September 29, 2025, 63.5% of patients in the combination arm remained on treatment vs 33.2% of those in the control arm.

What were the PFS, subgroup, and overall survival results with sac-TMT plus pembrolizumab?

The PFS benefit was consistent across PD-L1 and histology subgroups. Among patients with a PD-L1 TPS of at least 50%, the HR was 0.47 (95% CI, 0.29-0.77); the median PFS was NR (95% CI, NE-NE) with the sac-TMT combination (n = 83) vs 9.5 months (95% CI, 6.9-13.8) with the monotherapy (n = 82). Among those with a TPS ranging from 1% to 49%, the HR was 0.28 (95% CI, 0.19-0.41), with a median PFS of NR (95% CI, 11.1-NE) and 4.3 months (95% CI, 2.9-5.5) in the respective arms (n = 125; n = 123).

By histology, the HR was 0.28 (95% CI, 0.18-0.43), with a median PFS that was NR (95% CI, 13.6-NE) with the combination (n = 123) vs 6.6 months (95% CI, 4.3-8.7) with the monotherapy (n = 124) in those with nonsquamous disease. In those with squamous disease, the HR was 0.44 (95% CI, 0.29-0.66) with a median PFS of NR (95% CI, 8.3-NE) vs 5.5 months (95% CI, 4.1-7.0) in the respective arms (n = 85; n = 80). A forest plot showed benefit across most subgroups; the liver metastases subgroup crossed unity (HR, 0.68; 95% CI, 0.30-1.52), which Zhou attributed to small patient numbers.

The combination also improved response. The ORR was 70.2% with sac-TMT plus pembrolizumab vs 42.0% with pembrolizumab alone in the intention-to-treat population, equating to a 28.3-percentage-point difference between the arms. Moreover, the deep response rates, defined as at least 50% reduction in target-lesion sum of diameters, were 49.0% vs 25.9%, respectively, in the ITT population; this translated to a 23.2-percentage-point difference between the groups. Responses were also more durable with the combination, with an HR of 0.47 (95% CI, 0.27-0.82); 12-month DOR rates were 77.7% and 59.4%, respectively.

OS data were immature and analyzed descriptively at the PFS interim analysis, according to Zhou. A favorable trend was observed, with 33 deaths (15.9%) in the combination arm vs 54 (26.3%) in the control arm. The median OS at the time of the analysis was NR (95% CI, NE-NE) in the combination arm (n = 208) vs 14.5 months (95% CI, 14.5-NE) in the monotherapy arm (n = 205; HR, 0.55; 95% CI, 0.36-0.85). The 12-month OS rates in the respective arms were 80.4% and 68.9%.

What is the safety profile of sac-TMT plus pembrolizumab in PD-L1+ NSCLC?

The median duration of exposure was 8.9 months for sac-TMT and 8.3 months for pembrolizumab in the combination arm; it was 5.1 months for pembrolizumab in the control arm. Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 55.3% of patients in the combination arm vs 31.4% in the control arm, and serious TEAEs were reported in 38.9% vs 28.9% of patients, respectively. Zhou attributed the higher rate of grade 3 or higher events primarily to the expected hematologic toxicity of sac-TMT.

The most common TEAEs in the combination arm included anemia (any grade, 87.5%; grade ≥3, 9.1%), alopecia (65.9%; 0%), decreased white blood cell count (46.2%; 8.7%), decreased neutrophil count (44.7%; 17.3%), and stomatitis (40.4%; 5.3%).

Adverse effects of special interest (AEOSI) were consistent with the known profiles of the individual agents, and no new safety signals were identified. Sac-TMT AEOSI included anemia (any grade, 87.0%; grade ≥3, 9.1%), decreased neutrophil count (45.2%; 19.2%), stomatitis (44.2%; 6.3%), ocular surface toxicity (14.4%; 0%), and infusion-related reaction (5.8%; 0%).

Pembrolizumab AEOSI comprised hypothyroidism (any grade, 13.5%; grade ≥ 3, 0%), pneumonitis (12.5%; 2.9%), hyperthyroidism (7.2%; 0%), infusion reaction (5.8%; 0%), severe skin reactions (2.9%; 2.9%), and adrenal insufficiency (2.4%; 1.4%).

TEAEs led to discontinuation of sac-TMT or pembrolizumab for 3.8% and 5.3% of those in the combination, and discontinuation of pembrolizumab for 4.9% of those in the control arm. They resulted in death for 5 patients (2.4%) in the combination arm vs 13 (6.4%) in the control arm. No treatment-related deaths were attributed to sac-TMT, according to Zhou.

What else should be known about sac-TMT in NSCLC?

It was first announced that sac-TMT plus pembrolizumab improved PFS vs pembrolizumab alone in patients with PD-L1–positive NSCLC in November 2025.³ The combination previously received breakthrough therapy designation in China for the first-line treatment of PD-L1–positive NSCLC.⁴ In May 2026, Kelun-Biotech announced that China's National Medical Products Administration had accepted for review a supplemental new drug application for sac-TMT plus pembrolizumab in this setting, based on data from OptiTROP-Lung05.⁵

Disclosures: Zhou disclosed serving in a leadership role with IASLC; receiving honoraria from Akeso Biopharma, Alice, Amoy Diagnostics, Anheart Therapeutics, Hengrui Therapeutics, Innovent Biologics, Lilly, Luye Pharma, Merck Sharp & Dohme, QiLu Pharmaceutical, Sanofi, and TopAlliance BioScience; and serving in a consulting or advisory role for Amoy Diagnostics, Hengrui Therapeutics, Innovent Biologics, QiLu Pharmaceutical, and Top Alliance BioScience.

References

1. Zhou C, Xiong A, Yao W, et al. Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab versus pembrolizumab as first-line treatment for PD-L1-positive advanced non-small cell lung cancer (NSCLC): results from the randomized phase 3 OptiTROP-Lung05 study. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 8506.
2. Xiong A, Yao W, Zheng W, et al. Sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab in PD-L1-positive advanced non-small-cell lung cancer (OptiTROP-Lung05): interim analysis of a randomised, open-label, phase 3 trial. Lancet. Published online May 29, 2026. Accessed May 29, 2026. doi:10.1016/S0140-6736(26)00968-2
3. Kelun-Biotech announces phase 3 trial of sac-TMT in combination with Keytruda (pembrolizumab) as first-line treatment for PD-L1–positive NSCLC met primary endpoint. News Release. PR Newswire. November 24, 2025. Accessed May 29, 2026. https://www.prnewswire.com/news-releases/kelun-biotech-announces-phase-iii-trial-of-sac-tmt-in-combination-with-keytruda-pembrolizumab-as-first-line-treatment-for-pd-l1-positive-nsclc-met-primary-endpoint-302624279.html
4. Kelun-Biotech announces breakthrough therapy designation granted in China for sacituzumab tirumotecan (sac-TMT) in combination with immunotherapy pembrolizumab for first-line treatment of PD-L1-positive NSCLC. News release. Sichuan Kelun-Biotech Biopharmaceutical Co. January 5, 2026. Accessed May 29, 2026. https://en.kelun-biotech.com/newsCenter.aspx?mid=18
5. Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. The sNDA for sacituzumab tirumotecan (sac-TMT) in combination with pembrolizumab as first-line treatment for PD-L1-positive NSCLC accepted for review by NMPA. News release. May 8, 2026. Accessed May 29, 2026. https://www.prnewswire.com/news-releases/the-snda-for-sacituzumab-tirumotecan-sac-tmt-in-combination-with-pembrolizumab-as-firstline-treatment-for-pd-l1-positive-nsclc-accepted-for-review-by-nmpa-302766841.html